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| United States Patent |
6,207,675
|
|
Carry
, et al.
|
March 27, 2001
|
Pyrrole derivatives, their preparation and pharmaceutical compositions
containing them
Abstract
The invention concerns pyrrole derivatives of general formula (I) useful
for treatment and prevention of diseases in which are involved viruses of
the herpes family and/or cytokines in particular TNF.alpha..
##STR1##
| Inventors:
|
Carry; Jean-Christophe (Meudon, FR);
Mignani; Serge (Chatenay Malabry, FR);
Nemecek; Conception (Thiais, FR)
|
| Assignee:
|
Rhone-Poulenc Rorer S.A. (Antony, FR)
|
| Appl. No.:
|
319773 |
| Filed:
|
June 11, 1999 |
| PCT Filed:
|
December 10, 1997
|
| PCT NO:
|
PCT/FR97/02248
|
| 371 Date:
|
June 11, 1999
|
| 102(e) Date:
|
June 11, 1999
|
| PCT PUB.NO.:
|
WO98/25925 |
| PCT PUB. Date:
|
June 18, 1998 |
Foreign Application Priority Data
| Current U.S. Class: |
514/299; 546/112; 546/183 |
| Intern'l Class: |
A61K 31//437; 7/; A61P 31//22; 7/; C07D 471//04 |
| Field of Search: |
514/299
546/112,183
|
References Cited
U.S. Patent Documents
| 4684658 | Aug., 1987 | Fabre | 514/338.
|
| Foreign Patent Documents |
| 0522944A | Jan., 1993 | EP.
| |
| 2735476A | Dec., 1996 | FR.
| |
Primary Examiner: Huang; Evelyn Mei
Attorney, Agent or Firm: Finnegan, Henderson, Farabow, Garrett, Dunner, L.L.P.
Claims
What is claimed is:
1. A pyrrole compound having the following formula (I), its stereoisomer,
salt, or a mixture thereof:
##STR8##
in which
R.sub.1 is chosen from carboxamide, cyano, carboxyl, alkyloxycarbonyl,
acetyl and imidazolylcarbonyl radicals,
R.sub.3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and
hydroxyl radicals, and
Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, and
a) the bond - - - is a single bond,
R.sub.2 is chosen from a hydrogen atom, halogen atoms, and cyano, alkyl,
alkyloxy and trihalomethyl radicals,
R.sub.4 is a hydrogen atom, and
R.sub.5 is chosen from hydroxyl, alkyloxy, amino and haloacylamino
radicals,
or alternatively
b) the bond - - - a is a double bond, and
R.sub.2 is chosen from a hydrogen atom, halogen atoms, and cyano, alkyl,
alkyloxy, alkenyl and trihalomethyl radicals,
R.sub.4 is chosen from a hydrogen atom, halogen atoms, alkyloxy radicals
and alkylthio radicals which are unsubstituted or substituted with
carboxyl, alkyloxycarbonyl, amino, alkylamino or dialkylamino in which the
alkyl parts optionally form, with the nitrogen atom to which they are
attached, phthalimido or a 4- to 6-membered heterocycle which optionally
has another heteroatom chosen from nitrogen, oxygen and sulphur, and
2(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylsulphanyl, and
R.sub.5 is a hydrogen atom,
wherein R.sub.2 is not chlorine when simultaneously R.sub.4 and R.sub.5 are
hydrogen, and when R.sub.1 is cyano or carboxamido, and Het-R.sub.3 is
3-pyridyl optionally substituted with fluorine at the 2 position, or
alternatively simultaneously when R.sub.4 is halogen, R.sub.5 is hydrogen,
and when R.sub.1 is cyano or carboxamido and Het-R.sub.3 is 3-pyridyl
substituted with methyl, chlorine or fluorine at the 2 position or when
R.sub.1 is alkyloxycarbonyl or acetyl and when Het-R.sub.3 is 3-pyridyl,
and wherein said alkyl radicals are straight or branched and contain from 1
to 4 carbon atoms and said acyl and alkenyl radicals are straight or
branched and contain from 2 to 4 carbon atoms.
2. A pyrrole compound according to claim 1, wherein said pyrrole compound
is chosen from:
2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamid
e,
2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitri
le,
methyl
2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxyla
te,
1-acetyl-2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine,
2-chloro-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carbonitrile,
methyl
2-chloro-8-hydroxy-3-(2-chloropyridin-3-yl)5,6,7,8-tetrahydroindolizine-1-
carboxylate,
1-acetyl-2-chloro-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-chloro-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxamide,
2-chloro-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carbonitrile,
methyl
2-chloro-8-hydroxy-3-(2-fluoropyridin-3-yl)5,6,7,8-tetrahydroindolizine-1-
carboxylate,
1-acetyl-2-chloro-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamid
e,
2-chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitri
le,
methyl
2-chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxyla
te,
1-acetyl-2chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine,
2-chloro-8-methoxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxamide,
2-chloro-8-methoxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tretrahydroindolizine-1
-carbonitrile,
methyl
2-chloro-8-methoxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxylate,
1-acetyl-2-chloro-8-methoxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-chloro-8-methoxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxamide,
2-chloro-8-methoxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carbonitrile,
methyl
2-chloro-8-methoxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxylate,
1-acetyl-2-chloro-8-methoxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-cyano-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide
,
2-cyano-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitril
e,
methyl
2-cyano-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxylat
e,
1-acetyl-2-cyano-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine,
2-cyano-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-c
arboxamide,
2-cyano-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-c
arbonitrile,
methyl
2-cyano-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxylate,
1-acetyl-2-cyano-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindol
izine,
2-cyano-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-c
arboxamide,
2-cyano-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-c
arbonitrile,
methyl
2-cyano-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxylate,
1-acetyl-2-cyano-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindol
izine,
2-methoxy-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxami
de,
2-methoxy-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitr
ile,
methyl
2-methoxy-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxyl
ate,
1-acetyl-2-methoxy-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine,
2-methoxy-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxamide,
2-methoxy-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carbonitrile,
methyl
2-methoxy-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-
1-carboxylate,
1-acetyl-2-methoxy-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroind
olizine,
2-methoxy-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxamide,
2-methoxy-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carbonitrile,
methyl
2-methoxy-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-
1-carboxylate,
1-acetyl-2-methoxy-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroind
olizine,
2-methyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamid
e,
2-methyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitri
le,
methyl
2-methyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxyla
te,
1-acetyl-2-methyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine,
2-methyl-8-hydroxy-3-(2-chloropyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-c
arboxamide,
2-methyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carbonitrile,
methyl
2-methyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxylate,
1-acetyl-2-methyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-methyl-8-hydroxy-3-(2-fluoropyridin-3-yl)5,6,7,8-tetrahydroindolizine-1-c
arboxamide,
2-methyl-8-hydroxy-3-(2-fluoropyridin-3-yl)5,6,7,8-tetrahydroindolizine-1-c
arbonitrile,
methyl
2-methyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxylate,
1-acetyl-2-methyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-trifluoromethyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-c
arboxamide,
2-trifluoromethyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-c
arbonitrile,
methyl
2-trifluoromethyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-
carboxylate,
1-acetyl-2-trifluoromethyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindol
izine,
2-trifluoromethyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine-1-carboxamide,
2-trifluoromethyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine-1-carbonitrile,
methyl
2-trifluoromethyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroind
olizine-1-carboxylate,
1-acetyl-2-trifluoromethyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetra
hydroindolizile,
2-trifluoromethyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine-1-carboxamide,
2-trifluoromethyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine-1-carbonitrile,
methyl
2-trifluoromethyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroind
olizine-1-carboxylate,
1-acetyl-2-trifluoromethyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetra
hydroindolizine,
methyl 2-chloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-chloro-3-pyridin-3-yl-5,6-dihydroindolizine,
2-chloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-chloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-chloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-chloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
methyl
2-chloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-chloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2-chloro-7-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-chloro-7-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-chloro-7-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-chloro-7-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine,
2-chloro-7-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxa
mide,
2-chloro-7-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboni
trile,
methyl
2-chloro-7-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbox
ylate,
1-acetyl-2-chloro-7-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2-chloro-7-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxa
mide,
2-chloro-7-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboni
trile,
methyl
2-chloro-7-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carbox
ilate,
1-acetyl-2-chloro-7-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl
2,7-dichloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2,7-dichloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
methyl
2,7-dichloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2,7-dichloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2-cyano-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-cyano-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl 2-cyano-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-cyano-3-pyridin-3-yl-5,6-dihydroindolizine,
2-cyano-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-cyano-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-cyano-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-cyano-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2-cyano-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-cyano-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-cyano-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-cyano-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-methoxy-3-pyridin-3-yl-5,6dihydroindolizine-1-carbonitrile,
methyl 2-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine,
2-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2-methyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-methyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl 2-methyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methyl-3-pyridin-3-yl-5,6-dihydroindolizine,
2-methyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-methyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-methyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methyl-3-(2-chloropyridin-3-yl)-5,6dihydroindolizine,
2-methyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-methyl-3-(2-fluoropyridin-3-yl)5,6-dihydroindolizine-1-carbonitrile,
methyl
2-methyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2-trifluoromethyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-trifluoromethyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-trifluoromethyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-trifluoromethyl-3-pyridin-3-yl-5,6-dihydroindolizine,
2-trifluoromethyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxam
ide,
2-trifluoromethyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonit
rile,
methyl
2-trifluoromethyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxy
late,
1-acetyl-2-trifluoromethyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2-trifluoromethyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxam
ide,
2-trifluoromethyl-3-(2-fluoropyridin-3-yl)5,6-dihydroindolizine-1-carbonitr
ile,
methyl
2-trifluoromethyl-3-(2-fluoropyridin-3-yil5,6-dihydroindolizine-1-carboxyl
ate, and
1-acetyl-2-trifluoromethyl-3-(2-fluoropyridin-3-yl)5,6-dihydroindolizine.
3. A pyrrole compound according to claim 1, said compound having the
following formula (VI):
##STR9##
in which:
Hal is a halogen atom, and
a) the bond - - - is a double bond,
R.sub.3 is chosen from a hydrogen atom and halogen atoms,
R.sub.4 is chosen from a hydrogen atom, halogen atoms, alkyloxy radicals,
alkylthio radicals unsubstituted or substituted with carboxyl or
alkylamino in which the alkyl parts optionally form, with the nitrogen
atom to which they are attached, a 4- to 6-membered heterocycle which
optionally has another heteroatom chosen from nitrogen, oxygen and
sulphur, and 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylsulphanyl, and
R.sub.5 is a hydrogen atom,
or alternatively
b) the bond - - - is a single bond,
R.sub.3 and R.sub.4 are hydrogen atoms, and
R.sub.5 is chosen from hydroxyl and alkyloxy radicals,
wherein said alkyl radicals are straight or branched and contain from 1 to
4 carbon atoms.
4. A pyrrole compound according to claim 3, wherein in said formula (VI):
Hal is a chlorine atom, and
a) the bond - - - is a double bond,
R.sub.3 is chosen from a hydrogen atom and a chlorine atom,
R.sub.4 is chosen from hydrogen, chlorine, methoxy, methylthio,
2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylsulphanyl, and
2-aminoethylsulphanyl, and
R.sub.5 is hydrogen,
or alternatively
b) the bond - - - is a single bond,
R.sub.3 and R.sub.4 are hydrogen, and
R.sub.5 is chosen from hydroxyl and methoxy.
5. A pyrrole compound according to claim 1, wherein said pyrrole compound
is
2-chloro-8-hydroxy-3-(pyridin-3-yl)5,6,7,8-tetrahydroindolizine-1-carboxam
ide.
6. A pyrrole compound according to claim 1, wherein said pyrrole compound
is
2-chloro-8-methoxy-3-(pyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-carboxa
mide.
7. A pyrrole compound according to claim 1, wherein said pyrrole compound
is
2-chloro-7-methoxy-3-(pyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide.
8. A pyrrole compound according to claim 1, wherein said pyrrole compound
is 2,7-dichloro-3-(pyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide.
9. A process for making a pyrrole compound having the following formula
(I), its stereoisomer, salt, or a mixture thereof:
##STR10##
in which
R.sub.1 is chosen from carboxamide, cyano, carboxyl, alkyloxycarbonyl,
acetyl and imidazolylcarbonyl radicals,
R.sub.3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and
hydroxyl radicals, and
Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, and
a) the bond - - - is a single bond,
R.sub.2 is chosen from a hydrogen atom, halogen atoms, cyano, alkyl,
alkyloxy and trihalomethyl radicals,
R.sub.4 is a hydrogen atom, and
R.sub.5 is chosen from hydroxyl, alkyloxy, amino and haloacylamino
radicals,
or alternatively
b) the bond - - - is a double bond, and
R.sub.2 is chosen from a hydrogen atom, halogen atoms, cyano, alkyl,
alkyloxy, alkenyl and trihalomethyl radicals,
R.sub.4 is chosen from a hydrogen atom, halogen atoms, alkyloxy radicals
and alkylthio radicals which are unsubstituted or substituted with
carboxyl, alkyloxycarbonyl, amino, alkylamino or dialkylamino in which the
alkyl parts optionally form, with the nitrogen atom to which they are
attached, phthalimido or a 4- to 6-membered heterocycle which optionally
has another heteroatom chosen from nitrogen, oxygen and sulphur, and
R.sub.5 is a hydrogen atom,
wherein R.sub.2 is not chlorine when simultaneously R.sub.4 and R.sub.5 are
hydrogen, and when R.sub.1 is cyano or carboxamido, and Het-R.sub.3 is
3-pyridyl optionally substituted with fluorine at the 2 position, or
alternatively when simultaneously R.sub.4 is halogen, R.sub.5 is hydrogen,
and when R.sub.1 is cyano or carboxamido and Het-R.sub.3 is 3-pyridyl
substituted with methyl, chlorine or fluorine at the 2 position or when
R.sub.1 is alkyloxycarbonyl or acetyl and when Het-R.sub.3 is 3-pyridyl,
and wherein said alkyl radicals are straight or branched and contain from 1
to 4 carbon atoms and said acyl and alkenyl radicals are straight or
branched and contain from 2 to 4 carbon atoms,
said process comprising preparing a nitrile intermediate of the following
formula (IV):
##STR11##
in which Het, R.sub.2 and R.sub.3 are defined as above, by
reacting an acrylic derivative of the following formula (II):
##STR12##
in which R.sub.2 is chosen from a hydrogen atom and cyano, alkyl, alkyloxy
and trihalomethyl radicals, R'.sub.1 is chosen from cyano and
alkyloxycarbonyl radicals, and Hal is a halogen atom,
with an acid of the following formula (III):
##STR13##
in which Het and R.sub.3 are defined as above,
introducing said double bond, said radicals R.sub.4 and R.sub.5, and/or
said radical R.sub.2, and
optionally converting said nitrile intermediate to an amide, an acid, an
ester, an imidazole-containing radical or an acetyl radical,
or optionally converting an ester radical to an acid, an
imidazole-containing radical or an acetyl radical, and
optionally separating the resulting compound into its stereoisomeric forms
and/or converting the resulting compound to a salt.
10. A pharmaceutical composition comprising an effective amount of at least
one pyrrole compound of the following formula (I):
##STR14##
in which
a) the bond - - - is a single bond,
R.sub.1 is chosen from carboxamide, cyano, carboxyl, alkyloxycarbonyl,
acetyl and imidazolylcarbonyl radicals,
R.sub.3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and
hydroxyl radicals, and
Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, and
R.sub.2 is chosen from a hydrogen atom, halogen atoms, cyano, alkyl,
alkyloxy and trihalomethyl radicals,
R.sub.4 is a hydrogen atom, and
R.sub.5 is chosen from hydroxyl, alkyloxy, amino and haloacylamino
radicals,
or alternatively
b) the bond - - - is a double bond, and
R.sub.2 is chosen from a hydrogen atom, halogen atoms, cyano, alkyl,
alkyloxy, alkenyl and trihalomethyl radicals,
R.sub.4 is chosen from alkyloxy radicals and alkylthio radicals which are
unsubstituted or substituted with carboxyl, alkyloxycarbonyl, amino,
alkylamino or dialkylamino in which the alkyl parts optionally form, with
the nitrogen atom to which they are attached, phthalimido or a 4- to
6-membered heterocyde which optionally has another heteroatom chosen from
nitrogen, oxygen and sulphur,
R.sub.5 is a hydrogen atom,
R.sub.1 is chosen from carboxamido, cyano, carboxyl, alkyloxycarbonyl,
acetyl and imidazolylcarbonyl radicals,
R.sub.3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and
hydroxyl radicals, and
Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, or
R.sub.2 is chosen form a hydrogen atom, a bromine atom, an iodine atom, a
fluorine atom, cyano, alkyl, alkyloxy, alkenyl, and trihalomethyl
radicals,
R.sub.4 is chosen from a hydrogen atom and halogen atoms,
R.sub.5 is a hydrogen atom,
R.sub.1 is chosen from carboxamido, cyano, carboxyl, alkyloxycarbonyl,
acetyl and imidazolylcarbonyl radicals,
R.sub.3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and
hydroxyl radicals, and
Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, or
R.sub.2 is a chlorine atom,
R.sub.4 is chosen from a hydrogen atom and halogen atoms,
R.sub.5 is a hydrogen atom,
R.sub.1 is chosen from carboxyl and imidazolylcarbonyl radicals,
R.sub.3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and
hydroxyl radicals, and
Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, or
R.sub.2 is a chlorine atom,
R.sub.4 is chosen from a hydrogen atom and halogen atoms,
R.sub.5 is a hydrogen atom,
R.sub.1 is chosen from carboxamido, cyano, alkyloxycarbonyl and acetyl
radicals, and
R.sub.3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and
hydroxyl radicals, and
Het is chosen from pyridyl-2, pyridyl-4, pyridyl N-oxide and thiazolyl
radicals, or
R.sub.3 is chosen from a bromine atom, an iodine atom, and a hydroxyl
radical, and
Het is pyridyl-3,
wherein said alkyl radicals are straight or branched and contain from 1 to
4 carbon atoms and said acyl and alkenyl radicals are straight or branched
and contain from 2 to 4 carbon atoms,
together with a pharmaceutically acceptable carrier.
11. A process according to claim 9, wherein said Hal is chlorine.
Description
This application is the national phase of PCT/FR97/02248, filed Dec. 10,
1997.
The present invention relates to new pyrrole derivatives of general
formula:
##STR2##
which are useful in the treatment and prevention of conditions in which
viruses of the herpes family are involved, and/or in which cytokines,
including TNF.sub..alpha. (Tumour Necrosis Factor alpha), are involved.
Viruses of the herpes family are responsible for numerous conditions, some
of which can be very serious. It comprises in particular the group
.alpha., .beta. and .gamma. herpesviruses including the herpes simplex
viruses 1 and 2, varicella-zoster, cytomegalovirus (CMV), herpesviruses
types 6 and 7 (HHV-6 and HHV-7), Epstein-Barr virus and herpesvirus type 8
(HHV-8). The clinical forms due to a herpes simplex infection can vary
from benign forms such as herpes labialis to more serious forms such as
genital herpes. Herpes simplex may even be responsible for encephalitis
putting the patient's life at risk. Varicella-zoster is the virus
responsible for varicella and zona, it may also be responsible for more
serious conditions including encephalitis. Cytomegalovirus infections are
in general a symptomatic in healthy subjects, but can be the cause of
morbidity [retinitis (which may lead to blindness), pneumopathies and the
like] and of mortality in immunosuppressed subjects (patients suffering
from AIDS or any other immunodeficiency, for example after organ
transplantation or after anticancer chemotherapy). The cytomegalovirus is
also responsible for severe clinical manifestations for the foetus or
newborn in the case of a primary infection during pregnancy or during
seropositive blood transfusion into a seronegative newborn. The
herpesviruses HHV-6 and 7 are responsible for roseola and can be
reactivated in immunosuppressed subjects. The HHV-8 virus is involved in
Kaposi's sarcoma.
The treatments existing up until now are likely to cause serious side
effects. Furthermore, for some of these viruses, the treatments can most
often only be used by the intravenous route.
Cytokines (including TNF.sub..alpha.) are capable of activating various
viruses and/or retroviruses, for example the cytomegalovirus or the Human
Immuno-deficiency Virus (HIV), and are also capable of activating cellular
genes, in particular those involved in inflammatory processes, such as the
genes for chemokines, cytokines and adhesion molecules.
In European Applications EP 118 321, EP 147 317 and EP 124 384 and in
French Application 2 539 417, there have been described pyrrole
derivatives having an antithrombotic activity or serving as intermediates
for the preparation of antithrombotic derivatives. Pyrrole derivatives
having an anti-TNF ativity have been described in French Application 2 735
476.
In the general formula (I),
R.sub.1 is a carboxamide, cycano, carboxyl, alkyloxycarbonyl, acetyl or
imidazolylcarbonyl radical,
R.sub.3 is a hydrogen or halogen atom, or an alkyl or hydroxyl radical, and
Het is a pyridyl, pyridyl N-oxide or thiazolyl radical, and
a) the bond - - - is a single bond,
R.sub.2 is a hydrogen or halogen atom, or a cyano, alkyl, al-kyloxy or
trihalomethyl radical,
R.sub.4 is a hydrogen atom, and
R.sub.5 is a hydroxyl, alkyloxy, amino or haloacylamino radical, or
alternatively
b) the bond - - - is a double bond, and
R.sub.2 is a hydrogen or halogen atom, or a cyano, alkyl, alkyloxy, alkenyl
or trihalomethyl radical,
R.sub.4 is a hydrogen or halogen atom or an alkyloxy or alkylthio radical
which are optionally substituted with carboxyl, alkyloxycarbonyl, amino,
alkylamino or dialkylamino in which the alkyl parts can form, with the
nitrogen atom to which they are attached, a 4- to 6-membered heterocycle
which may, in addition, comprise another heteroatom chosen from nitrogen,
oxygen or sulphur, or phthalimido, and
R.sub.5 is a hydrogen atom, it being understood that R.sub.2 cannot be
chlorine when simultaneously R.sub.4 and R.sub.5 are hydrogen, and when
R.sub.1 is cyano or carboxamido, and Het-R.sub.3 is 3-pyridyl optionally
substituted with fluorine at the 2 position, or alternatively when
simultaneously R.sub.4 is halogen, R.sub.5 is hydrogen, and when R.sub.1
is cyano or carboxamido and Het-R.sub.3 is 3-pyridyl substituted with
methyl, chlorine or fluorine at the 2 position or when R.sub.1 is
alkyloxycarbonyl or acetyl and when Het-R.sub.3 is 3-pyridyl,
the alkyl radicals being straight or branched and containing 1 to 4 carbon
atoms and the acyl and alkenyl radicals being straight or branched and
containing 2 to 4 carbon atoms.
According to the invention, the halogen atoms are chosen from fluorine,
chlorine, bromine or iodine.
According to the invention, the heterocycles are for example chosen from
the morpholine, thiomorpholine, piperidine, pyrrolidine, piperazine,
N-alkylpiperazine (for example N-methylpiperazine) or azetidine ring.
According to the invention, the preparation of the products of general
formula (I) is carried out by preparing a nitrile intermediate of general
formula:
##STR3##
in which Het, R.sub.2 and R.sub.3 are defined as above, by the action of an
acrylic derivative of general formula:
##STR4##
in which R.sub.2 is defined as above, with the exception of representing a
halogen atom, R'.sub.1 is a cyano or alkyloxycarbonyl radical, and Hal is
a halogen atom (for example a chlorine atom) on an acid of general
formula:
##STR5##
in which Het and R.sub.3 are defined as above, followed by the steps of
introducing the double bond and/or the radicals R.sub.4 and R.sub.5 and/or
optionally R.sub.2, and where appropriate converting the nitrile to an
amide, an acid, an ester, an imidazole-containing radical or an acetyl
radical, or alternatively, where appropriate, converting the ester radical
to an acid, an imidazole-containing radical or an acetyl radical, by any
known methods which do not alter the rest of the molecule.
By way of example, the known methods may be in particular methods described
in the patent applications cited above, or the methods described in the
examples which follow, or methods analogous to these methods.
The reaction of the product of general formula (II) with the acid of
general formula (III) is generally carried out using the acid salt (sodium
salt for example) in acetic anhydride at a temperature of between 80 and
130.degree. C., or in para-toluenesulphonyl chloride.
When it is desired to obtain the derivative for which R.sub.2 represents
cyano, the product obtained is subjected to treatment with
isocyanatosulphonyl chloride at a temperature of between 0 and 10.degree.
C. in an organic solvent such as acetonitrile.
When it is desired to obtain the derivative for which R.sub.2 represents
trihalomethyl or alkenyl, the derivative of general formula (IV) obtained
is treated beforehand according to the method described in French
Application 2 735 476, or by any method analogous thereto.
When it is desired to obtain the derivative of general formula (IV) for
which R.sub.2 represents a halogen atom, the halogenation of the
intermediate of general formula (IV) for which R.sub.2 is hydrogen is
carried out with an N-halosuccinimide, followed by a reduction of the
product obtained, for example by catalytic hydrogenation in an acidic
medium, in the presence of palladium on carbon.
The halogenation is carried out with 1 or 3 equivalents of
N-halosuccinimide (for example N-chlorosuccinimide). The procedure is
advantageously carried out in a chlorinated solvent (dichloromethane or
dichloroethane for example) or in a nitrile (acetonitrile for example) at
the reflux temperature of the reaction mixture.
When it is desired to obtain a derivative as defined in a), or for which -
- - is a double bond and R.sub.4 and R.sub.5 are hydrogen atoms, the
halogenation of the intermediate of general formula (IV) is carried out
with an N-halosuccinimide, followed by the reduction of the product
obtained, for example by catalytic hydrogenation in an acidic medium, in
the presence of palladium, so as to obtain an intermediate of general
formula:
##STR6##
in which Het, R.sub.2 and R.sub.3 are defined as above.
The derivative of general formula (V) can be either reduced in order to
obtain a derivative for which R.sub.5 is a hydroxyl radical and then,
where appropriate, dehydrated in order to obtain the product for which - -
- is a double bond and R.sub.4 and R.sub.5 are hydrogen atoms, or
converted to an imine and then reduced to an amine according to known
methods, or treated with a trialkyl ester and then reduced, for example,
by catalytic hydrogenation in an acidic medium and in the presence of
palladium.
The halogenation is carried out with 4 or 5 equivalents of
N-halosuccinimide (for example N-chlorosuccinimide), according to whether
the intermediate of general formula (IV) for which R.sub.2 is hydrogen or
otherwise is used as starting material. The procedure is advantageously
carried out in a chlorinated solvent (dichloromethane or dichloroethane
for example) or in a nitrile (acetonitrile for example) at the reflux
temperature of the reaction mixture.
The reduction of the ketone functional group to a hydroxyl can be carried
out with an alkali metal borohydride, for example sodium cyanoborohydride,
in an alcoholic medium at a temperature of between 20 and 40.degree. C.
The dehydration can be carried out with an acid such as in particular
p-toluenesulphonic acid in an organic solvent such as toluene for example,
at the reflux temperature of the reaction mixture.
The conversion of the ketone functional group to the imine can be obtained
for example by application or adaptation of the methods described in Org.
Synth., 5, 191; Org. Synth., 54, 46 or Synthesis 6(2), 629 1985). The
reduction to an amine can be carried out by application or by analogy with
the methods described in J. Org. Chem., 51, 3635 (1986) or J. Med. Chem.,
7, 381 (1964).
The conversion of the ketone functional group to an alkyloxy can be carried
out by treating with a trialkyl orthoformate, for example trimethyl
orthoformate, in an alcoholic medium at the reflux temperature of the
reaction mixture.
When it is desired to obtain a derivative as defined in b), the
halogenation of the intermediate of general formula (IV) is carried out
with an N-halosuccinimide, followed where appropriate by treatment with an
alcoholate or a thiolate.
The halogenation is carried out with 2 or 3 equivalents of
N-halosuccinimide, according to whether or not it is desired to obtain a
product for which R.sub.2 is a halogen atom (from the corresponding
derivative for which R.sub.2 is a hydrogen atom). The procedure is
advantageously carried out in a chlorinated solvent (dichloromethane or
dichloroethane for example) or in a nitrile (acetonitrile for example) at
the reflux temperature of the reaction mixture.
The treatment with an alcoholate (for example sodium methoxide) or with a
thiolate (for example sodium thiomethoxide) is carried out in toluene, at
the reflux temperature of the reaction mixture.
The hydrolysis of the nitrile to an amide is carried out according to known
methods, in particular by heating in an alkaline medium in an organic
solvent, for example t-butanol at a temperature of between 30 and
85.degree. C., or in a concentrated acidic medium at a temperature of
between 20 and 100.degree. C.
The hydrolysis of the ester or of the nitrile to an acid is carried out
according to known methods, in particular in a basic medium in an alcohol
with a high boiling point, for example in the presence of potassium
hydroxide in ethylene glycol, at a temperature of between 100.degree. C.
and the reflux temperature of the reaction mixture.
The conversion of the acid functional group Hto an alkyloxycarbonyl radical
is carried out by the usual esterification methods which do not alter the
rest of the molecule, in particular by application or adaptation of the
methods described in Tetrahedron, 33, 683 (1977), Tetrahedron Letters,
4475 (1978) or Bull. Soc. Chim. Japan, 40, 2380 (1967).
The conversion of the acid functional group to an imidazole-containing
radical is carried out in a solvent such as tetrahydrofuran at a
temperature of between 20 and 40.degree. C.
The conversion to an acetyl radical is carried out using, as starting
material, the derivative for which R.sub.1 is carboxyl, by preparing the
acid halide and then by the action of a malonic derivative (for example
methyl malonate), followed by decarboxylation of the derivative obtained.
The procedure is carried out under the conditions described or by analogy
with the conditions described in Tetrahedron, 14, 321 (1961); Org. Synth.,
3, 169; J. Org. Chem., 50, 2622 (1987); Synthesis, 284 (1982).
The oxidation of the pyridyl radical to pyridyl N-oxide is carried out by
any oxidation method which does not alter the rest of the molecule. In
particular, the procedure is carried out by means of a peracid such as
m-chloroperbenzoic acid, in an alcoholic medium (ethanol for example) at a
temperature of between 15 and 30.degree. C.
When - - - is a single bond, the derivatives of general formula (I) exhibit
stereoisomeric forms. These forms are separated by known methods, in
particular by chromatography on a chiral phase. It is understood that the
present invention also relates to the stereoisomers of the products of
general formula (I) when these exist, as well as mixtures thereof.
The products according to the invention which carry an amino or alkylamino
radical may be converted to acid addition salts by known methods. It is
understood that these salts are also within the scope of the present
invention.
As examples of addition salts with pharmaceutically acceptable acids, there
may be mentioned the salts formed with inorganic acids (hydrochlorides,
hydrobromides, sulphates, nitrates, phosphates) or with organic acids
(succinates, fumarates, tartrates, acetates, propionates, maleates,
citrates, methanesulphonates, p-toluenesulphonates, isethionates, or with
substitution derivatives of these compounds).
The present invention also relates to the pyrrole derivatives of general
formula (I) in which when - - - is a double bond, R.sub.2 is a chlorine
atom when simultaneously R.sub.4 is hydrogen or halogen, R.sub.5 is
hydrogen, and when R.sub.1 is cyano, carboxamido, alkyloxycarbonyl or
acetyl, and Het-R.sub.3 is 3-pyridyl optionally substituted with methyl,
chlorine or fluorine at the 2 position [hereinafter called structure
(I')], for their use as a medicament. These products have in particular
proved very advantageous in the treatment and/or prophylaxis of conditions
in which a virus of the herpes family is involved, and/or in which TNF is
involved.
The action of the derivatives of general formula (I) on viruses of the
herpes family has been demonstrated in the techniques described by NEYTS
et al., Virology, 179, 41-50 (1990); Andrei et al., Eur. J. Clin.
Microbiol. Infect. Dis., 10, 1026-1033 (1991); or in the technique
described by Andrei et al., Eur. J. Clin. Microbiol. Infect. Dis., 11,
143-151 (1992), Reymen et al., Antiviral Res., 28, 343-357 (1995).
The technique used consists in the measurement of the cytopathogenic effect
of the herpesvirus and of its protection by the use of products of general
formula (I). The antiviral activity is assessed by measuring the IC.sub.50
(concentration necessary to inhibit 50% of the cytopathogenic effect
induced by the virus).
The activity of the products according to the invention on the human
cytomegalovirus has been studied on the Davis and AD-169 strains. On the
Davis strain, the products according to the invention proved active at
IC.sub.50 values of between 0.015 .mu.g/ml and 20 .mu.g/ml, and on the
AD-169 strain, the products according to the invention proved active at
IC.sub.50 values of between 0.02 .mu.g/ml and 20 .mu.g/ml.
By way of example, the results obtained in these techniques for 4 products
according to-the invention are given below:
TABLE I
AD-169 Davis strain
Example No. IC.sub.50 (.mu.g/ml) IC.sub.50 (.mu.g/ml)
1 1.15 0.5
0.32 0.5
2 0.5 0.43
0.86 0.72
7 [(R,S) form] 0.2 0.027
0.02 0.015
8 <0.2 <0.2
0.05 0.02
Moreover, no product manifests cytotoxicity in vitro (50% inhibition of
cell growth at the dose of 20 .mu.g/ml)
The inhibitory activity of the compounds according to the invention towards
the effects mediated by various cellular activators, including
TNF.sub..alpha., has been demonstrated in the following manner:
The effects of the derivatives according to the invention on the
reactivation of the HIV virus by TNF.sub..alpha. (10 Units/ml) or Phorbol
Myristate Acetate (PMA at 10.sup.-7 M) were studied in U1 cells derived
from the promonocytic line U937 [Folks et al., Science, 238, 800 (1987)].
Experimental Study:
The product to be studied is dissolved in dimethylformamide (DMF) or
dimethyl sulphoxide (DMSO). The stock solutions are stored at a
temperature of 4.degree. C. and diluted in culture medium on the day of
the experiment so that the solvent concentration is constant (0.1%).
The U1 cells are pretreated 5 hours before stimulation with product
concentrations ranging from 0.001 .mu.M to 10 .mu.M. Three days after
induction, the viral supernatant is collected and the reverse
transcriptase activity reflecting viral production is evaluated (SPA
test).
The reverse transcriptase activity is measured by known techniques, in
duplicate [Strebel et al., Nature, 328, 728 (1987)].
Some controls do not receive the activator. Other controls do not receive
the product to be studied. Others receive neither the product nor the
activator.
Results:
The decrease in viral production caused by the derivatives according to the
invention is significant and dose-dependent in the case of U1 cells
treated with TNF.sub..alpha. or with PMA. On day 3, a decrease of at least
50% in the production of reverse transcriptase is observed for the U1
cells stimulated with 10 units/ml of TNF.sub..alpha. and treated with a
concentration of 10 .mu.M of product.
Moreover, no cytotoxicity of the test products is observed on cell
viability at the concentration of 1 .mu.M.
In this method, the compounds according to the invention have proved active
at concentrations of between 0.01 .mu.M and 10 .mu.M.
Advantageous products are for example:
2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamid
e,
2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitri
le, methyl
2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxyla
te,
1-acetyl-2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine,
2-chloro-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxamide,
2-chloro-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carbonitrile,
methyl
2-chloro-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxylate,
1-acetyl-2-chloro-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-chloro-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxamide,
2-chloro-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carbonitrile,
methyl
2-chloro-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxylate,
1-acetyl-2-chloro-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamid
e,
2-chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitri
le,
methyl
2-chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetra-hydroindolizine-1-carboxyl
ate,
1-acetyl-2-chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine,
2-chloro-8-methoxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxamide,
2-chloro-8-methoxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carbonitrile,
methyl
2-chloro-8-methoxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxylate,
1-acetyl-2-chloro-8-methoxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-chloro-8-methoxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxamide,
2-chloro-8-methoxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carbonitrile,
methyl
2-chloro-8-methoxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxylate,
1-acetyl-2-chloro-8-methoxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-cyano-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide
,
2-cyano-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitril
e,
methyl
2-cyano-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxylat
e,
1-acetyl-2-cyano-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine,
2-cyano-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-c
arboxamide,
2-cyano-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-c
arbonitrile,
methyl
2-cyano-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxylate,
1-acetyl-2-cyano-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindol
izine,
2-cyano-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-c
arboxamide,
2-cyano-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-c
arbonitrile,
methyl
2-cyano-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxylate,
1-acetyl-2-cyano-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindol
izine,
2-methoxy-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxami
de,
2-methoxy-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitr
ile,
methyl
2-methoxy-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxyl
ate,
1-acetyl-2-methoxy-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine,
2-methoxy-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxamide,
2-methoxy-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carbonitrile,
methyl
2-methoxy-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-
1-carboxylate,
1-acetyl-2-methoxy-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroind
olizine,
2-methoxy-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxamide,
2-methoxy-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carbonitrile,
methyl
2-methoxy-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-
1-carboxylate,
1-acetyl-2-methoxy-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroind
olizine,
2-methyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamid
e,
2-methyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitri
le,
methyl
2-methyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxyla
te,
1-acetyl-2-methyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine,
2-methyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxamide,
2-methyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carbonitrile,
methyl
2-methyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxylate,
1-acetyl-2-methyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-methyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carboxamide,
2-methyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-
carbonitrile,
methyl
2-methyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1
-carboxylate,
1-acetyl-2-methyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine,
2-trifluoromethyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-c
arboxamide,
2-trifluoromethyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-c
arbonitrile,
methyl
2-trifluoromethyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-
carboxylate,
1-acetyl-2-trifluoromethyl-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindol
izine,
2-trifluoromethyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine-1-carboxamide,
2-trifluoromethyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine-1-carbonitrile,
methyl
2-trifluoromethyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroind
olizine-1-carboxylate,
1-acetyl-2-trifluoromethyl-8-hydroxy-3-(2-chloropyridin-3-yl)-5,6,7,8-tetra
hydroindolizine,
2-trifluoromethyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine-1-carboxamide,
2-trifluoromethyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroindo
lizine-1-carbonitrile,
methyl
2-trifluoromethyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetrahydroind
olizine-1-carboxylate,
1-acetyl-2-trifluoromethyl-8-hydroxy-3-(2-fluoropyridin-3-yl)-5,6,7,8-tetra
hydroindolizine,
2-chloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-chloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl 2-chloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-chloro-3-pyridin-3-yl-5,6-dihydroindolizine,
2-chloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-chloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-chloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-chloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2-chloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-chloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-chloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-chloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2-chloro-7-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-chloro-7-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-chloro-7-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-chloro-7-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine,
2-chloro-7-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxa
mide,
2-chloro-7-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboni
trile,
methyl
2-chloro-7-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbox
ylate,
1-acetyl-2-chloro-7-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2-chloro-7-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxa
mide,
2-chloro-7-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboni
trile,
methyl
2-chloro-7-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carbox
ylate,
1-acetyl-2-chloro-7-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl 2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine,
2,7-dichloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2,7-dichloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2,7-dichloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2,7-dichloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2,7-dichloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2,7-dichloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2,7-dichloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2,7-dichloro-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2-cyano-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-cyano-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl 2-cyano-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-cyano-3-pyridin-3-yl-5,6-dihydroindolizine,
2-cyano-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-cyano-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-cyano-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-cyano-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2-cyano-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-cyano-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-cyano-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-cyano-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl 2-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine,
2-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methoxy-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methoxy-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2-methyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-methyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl 2-methyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methyl-3-pyridin-3-yl-5,6-dihydroindolizine,
2-methyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-methyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-methyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2-methyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-methyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-methyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-methyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine,
2-trifluoromethyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide,
2-trifluoromethyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile,
methyl
2-trifluoromethyl-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxylate,
1-acetyl-2-trifluoromethyl-3-pyridin-3-yl-5,6-dihydroindolizine,
2-trifluoromethyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxam
ide,
2-trifluoromethyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carbonit
rile,
methyl
2-trifluoromethyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxy
late,
1-acetyl-2-trifluoromethyl-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine,
2-trifluoromethyl-3-(2-fluoropyridin-3--yl)-5,6-dihydroindolizine-1-carboxa
mide,
2-trifluoromethyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carbonit
rile,
methyl
2-trifluoromethyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine-1-carboxy
late,
1-acetyl-2-trifluoromethyl-3-(2-fluoropyridin-3-yl)-5,6-dihydroindolizine.
In particular, the products of formula:
##STR7##
for which:
Hal represents a halogen atom as defined above for R.sub.2, and
a) the bond - - - is a double bond,
R.sub.3 is a hydrogen or halogen atom as defined above for R.sub.3,
R.sub.4 is a hydrogen or halogen atom as defined above for R.sub.4, an
alkyloxy or alkylthio radical optionally substituted with carboxyl or
alkylamino in which the alkyl parts can form, with the nitrogen atom to
which they are attached, a 4- to 6-membered heterocycle which may, in
addition, comprise another heteroatom chosen from nitrogen, oxygen or
sulphur, or phthalimido, and
R.sub.5 is a hydrogen atom, or alternatively
b) the bond - - - is a single bond,
R.sub.3 and R.sub.4 are hydrogen atoms, and
R.sub.5 is a hydroxyl or alkyloxy radical, the alkyl radicals being
straight or branched and containing 1 to 4 carbon atoms, are more
particularly advantageous.
Among these products, according to a preferred aspect of the invention,
Hal represents a chlorine atom, and
a) the bond - - - is a double bond,
R.sub.3 is a hydrogen or chlorine atom,
R.sub.4 is hydrogen, chlorine, methoxy, methylthio,
2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylsulphanyl, or
2-aminoethylsulphanyl, and
R.sub.5 is hydrogen, or alternatively
b) the bond - - - is a single bond,
R.sub.3 and R.sub.4 are hydrogen, and
R.sub.5 is hydroxyl or methoxy.
Still more preferably, the following compounds may be mentioned;
2-chloro-8-hydroxy-3-(pyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-carboxam
ide,
2-chloro-3-(pyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
2-chloro-8-methoxy-3-(pyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-carboxam
ide,
2-chloro-7-methoxy-3-(pyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide,
and
2,7-dichloro-3-(pyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide.
The pharmaceutical compositions containing pyrrole derivatives of general
formula (I) and/or pyrrole derivatives of structure (I') are particularly
advantageous because of the fact that they find application in many
diseases of viral origin, particularly retinitis, pneumopathies,
encephalitis, digestive infections and encephalitis caused by CMV,
Kaposi's sarcoma, herpes labialis, genital herpes, herpetic encephalitis,
varicella, roseola, zonas, hepatitis (caused by cytomegalovirus),
ophthalmic infections or in the prophylaxis of the infection or of the
viral reactivation. It may also be highly advantageous in the treatment
and prevention of cardiovascular diseases, particularly in restenosis
which may follow an angioplasty.
Likewise, the pharmaceutical compositions containing pyrrole derivatives of
general formula (I) and/or pyrrole derivatives of structure (I') are also
particularly advantageous because of the fact that they find applications
in any of the pathologies involving cytokines including TNF.sub..alpha..
By way of example, there may be mentioned: osteoarticular diseases of
inflammatory origin, asthma, diabetes, cachexia (secondary to an infection
or to a tumour), diseases of the digestive system such as Crohn's disease
and ulcerohaemorrhagic rectocolitis, disorders of the central and/or
peripheral nervous system, immunological diseases including
graft-versus-host disease and allograft rejection, lesions due to
perfusion and/or ischaemia, and viral or infectious diseases including
pathologies related to HIV and to tuberculosis.
They are also advantageous for their applications in pathologies related to
IL-8 reactivated by TNF.sub..alpha., such as psoriasis, inflammatory
diseases of the digestive tube, respiratory distress syndrome, asthma,
lesions induced by a perfusion, thrombosis, glomerulonephritis, and
inflammatory osteoarticular pathologies.
They can also be used in pathologies involving adhesion molecules, for
example diseases of the cardiovascular system (in particular
artherosclerosis or thrombosis), lesions related to ischaemia-reperfusion,
neurological disorders, digestive, pulmonary or articular inflammatory
pathologies, immunological diseases including graft rejection.
The following examples, given with no limitation being implied, illustrate
the invention:
EXAMPLE 1
A suspension of 2.4 g of
3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide and 4.2 g of
N-chlorosuccinimide in 600 cm.sup.3 of acetonitrile is heated at the
reflux temperature of acetonitrile for 3 hours. The reaction mixture is
hydrolysed with 200 cm.sup.3 of water is and then extracted with 3 times
300 cm.sup.3 of ethyl acetate. The organic phases are dried over magnesium
sulphate and then concentrated to dryness under reduced pressure (2.7 kPa)
at a temprature close to 40.degree. C. 2.51 g of a yellow powder are
obtained, which powder is recrystallized from 65 cm.sup.3 of acetonitrile.
1.25 g of 2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide
are thus obtained in the form of a beige powder melting at 217.degree. C.
EXAMPLE 2
A mixture of 6 g of
2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide and 5,24 g
of sodium methoxide in 120 cm.sup.3 of toluene and 0.4 cm.sup.3 of
methanol is heated at the reflux temperature of toluene for 5 days. The
reaction mixture is hydrolysed with 100 cm.sup.3 of water and then
extracted with three times 100 cm.sup.3 of dichloromethane. The organic
phases are dried over magnesium sulphate and then concentrated to dryness
under reduced pressure (2.7 kPa) at a temperature close to 40.degree. C.
2.28 g of a yellow solid are obtained, which solid is chromatographed on a
column 5.7 cm in diameter containing 580 g of silica (0.02-0.045). The
elusion is carried out with a dichloromethane/ethyl acetate (80/20)
mixture, at a pressure of 150 kPa, collecting 50 cm.sup.3 fractions. The
homogeneous fractions are pooled and concentrated to dryness under reduced
pressure (2.7 kPa) at a temperature close to 40.degree. C. 1.16 g of a
yellow solid are obtained, which solid is recrystallized from 50 cm.sup.3
of acetonitrile. 0.524 g of
2-chloro-7-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide is
obtained in the form of a white solid melting at 228.degree. C.
3-Pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide is prepared as
described in European Patent Application EP 124 384.
EXAMPLE 3
A mixture of 0.616 g of
2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide and 0.28 g
of sodium thiomethoxide in 30 cm.sup.3 of dimethylformamide is heated at
57.degree. C. for 5 hours. The reaction mixture is poured into 250
cm.sup.3 of brine and then extracted with four times 80 cm.sup.3 of
dichloromethane. The organic phases are washed with three times 50
cm.sup.3 of brine, dried over magnesium sulphate and then concentrated to
dryness under reduced pressure (2.7 kPa) at a temperature close to
40.degree. C. 0.6 g of an ochre-coloured crystallized product is obtained.
This product is recrystallized from 75 cm.sup.3 of acetonitrile. 0.29 g of
2-chloro-3-pyridin-3-yl-7-methylthio-5,6-dihydroindolizine-1-carboxamide
is thus obtained in the form of a cream-coloured powder melting at
214.degree. C.
2,7-Dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide is prepared
as described in Example 1.
EXAMPLE 4
2.4 g of methyl 3-mercaptopropionate are dissolved in 100 cm.sup.3 of
dimethylformamide. 0.8 g of sodium hydride is added in small fractions,
and then 3.08 g of
2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide in 80
cm.sup.3 of dimethylformamide are poured in. The mixture is heated at
68.degree. C. for 2 hours 30 minutes, and then poured into 25 cm.sup.3 of
hydrochloric acid (4 N). The mixture is concentrated to dryness under
reduced pressure (1 kPa) at a temperature close to 60.degree. C. The
yellow residue obtained is taken up in 280 cm.sup.3 of water and 10
cm.sup.3 of hydrochloric acid (2 N), and then filtered and washed with
twice 5 cm.sup.3 of water. 1.1 g of
2-chloro-3-pyridin-3-yl-7-mercapto-5,6-dihydroindolizine-1-carboxamide are
thus obtained in the form of a yellow powder melting at 232.degree. C.
A mixture of 0.342 g of
2-chloro-3-pyridin-3-yl-7-mercapto-5,6-dihydroindolizine-1-carboxamide
hydrochloride, 0.414 g of potassium carbonate and 0.381 g of
N-(2-bromoethyl)phthalimide in 25 cm.sup.3 of dimethylformamide is heated
from 68.degree. C. to 105.degree. C. for 24 hours. The dimethylformamide
is concentrated to dryness under reduced pressure (2.7 kPa) at a
temperature close to 70.degree. C. The oil obtained is taken up in 200
cm.sup.3 of water and extracted with twice 100 cm.sup.3 of
dichloromethane. The organic phases are dried over magnesium sulphate and
then concentrated to dryness under reduced pressure (2.7 kPa) at a
temperature close to 50.degree. C. 0.26 g of an orange-coloured residue is
obtained which is chromatographed on a column 4 cm in diameter containing
6 g of silica (0.02-0.045). The elution is carried out with a
dichloromethane/methanol (99/1) mixture, collecting 15 cm.sup.3 fractions.
The homogeneous fractions are pooled and concentrated to dryness under
reduced pressure (2.7 kPa) at a temperature close to 40.degree. C. 0.11 g
of a yellow foam is thus obtained which is recrystallized from 12 cm.sup.3
of acetonitrile. 0.050 g of
2-chloro-3-pyridin-3-yl-7-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylsulp
hanyl]-5,6-dihydroindolizine-1-carboxamide is thus obtained in the form of
a yellow powder melting at 161.degree. C.
2,7-Dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide is prepared
as described in Example 1.
EXAMPLE 5
A mixture of 1.3 g of
2-chloro-3-pyridin-3-yl-7-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylsulp
hanyl]-5,6-dihydroindolizine-1-carboxamide and 1.16 cm.sup.3 of hydrazine
hydrate in 30 cm.sup.3 of ethanol is heated at the reflux temperature of
ethanol for 6 hours. The reaction mixture is concentrated to dryness under
reduced pressure (2.7 kPa) at a temperature close to 40.degree. C. The
cream-coloured solid obtained is taken up in 80 cm.sup.3 of water, and the
pH is brought to 1 by addition of hydrochloric acid (4 N). The mixture is
filtered and the solid is washed with twice 10 cm.sup.3 of water. The
clear yellow filtrate is brought to a pH of 10 by addition of sodium
carbonate. The oil formed is extracted with three times 100 cm.sup.3 of
dichloromethane. The organic phases are dried over magnesium sulphate and
then concentrated to dryness under reduced pressure (2.7 kPa) at a
temperature close to 40.degree. C. 0.6 g of an orange-coloured residue is
obtained which is chromatographed on a column 3 cm in diameter containing
150 g of silica (0.02-0.045). The elution is carried out with a
dichloromethane/methanol (50/50) mixture, collecting 20 cm.sup.3
fractions. The homogeneous fractions are pooled and concentrated to
dryness under reduced pressure (2.7 kPa) at a temperature close to
40.degree. C. 0.4 g of a beige gummy crystallized product is obtained
which is recrystallized from 25 cm.sup.3 of ethanol and 5 cm.sup.3 of
hydrochloric ethanol (5 N). 0.29 g of
7-(2-aminoethylsulphanyl)-2-chloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-
carboxamide dihydrochloride is thus obtained in the form of a yellow powder
melting at 175.degree. C.
2-Chloro-3-pyridin-3-yl-7-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylsulph
anyl-]-5,6-dihydroindolizine-1-carboxamide is prepared as described in
Example 4.
EXAMPLE 6
2,7-Dichloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide
is prepared as described in Example 1, but starting with 4.1 g of
3-(2-chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide and
6.3 g of N-chlorosuccinimide in 1000 cm.sup.3 of acetonitrile. 0.84 g of
2,7-dichloro-3-(2-chloropyridin-3-yl)-5,6-dihydroindolizine-1-carboxamide
is obtained in the form of white floccules melting at 262.degree. C.
3-(2-Chloropyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide is
described in Patent Application EP 124 384.
EXAMPLE 7
A mixture of 2.23 g of
3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 6.7 g of
N-chlorosuccinimide in 200 cm.sup.3 of acetonitrile is heated at the
reflux temperature of acetonitrile for 3 hours. The reaction mixture is
hydrolysed with 300 cm.sup.3 of water and then extracted with three times
250 cm.sup.3 of dichloromethane. The organic phases are dried over
magnesium sulphate and then concentrated to dryness under reduced pressure
(2.7 kPa) at a temperature close to 40.degree. C., and 2.84 g of residue
are chromatographed on a column 4 cm in diameter containing 400 g of
silica (0.04-0.063). The elution is carried out with ethyl acetate, at a
pressure of 150 kPa, collecting 60 cm.sup.3 fractions. the homogeneous
fractions are pooled and concentrated to dryness under reduced pressure
(2.7 kPa) at a temperature close to 40.degree. C. 1.67 g of a solid are
thus obtained, which solid is recrystallized from 7.5 cm.sup.3 of
acetonitrile. 650 mg of
2,7,7-trichloro-8-oxo-3-pyridin-3-yl-5,6,7,8-tetrahydro-indolizine-1-carbo
nitrile are obtained in the form of an orange-coloured powder melting at
220.degree. C.
A suspension of 10.14 g of
2,7,7-trichloro-8-oxo-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbon
itrile and 300 cm.sup.3 of acetic acid in 1000 cm.sup.3 of ethanol is
stirred under argon, and 3.06 g of 10% palladium on carbon in 50 cm.sup.3
of ethanol are added. The reaction mixture is bubbled with hydrogen for 2
hours at room temperature, and then filtered on No. 3 sintered glass
covered with Celite. The cake is washed with twice 50 cm.sup.3 of ethanol
and the filtrate is then concentrated to dryness under reduced pressure
(2.7 kPa) at a temperature close to 55.degree. C. An oily residue is taken
up in 150 cm.sup.3 of water and the pH is brought to 8-9 by addition of
sodium hydrogen carbonate. 7.08 g of
2-chloro-8-oxo-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile
are obtained in the form of a white solid melting at a temperature greater
than 260.degree. C.
10.33 g of
2-chloro-8-oxo-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile
in 70 cm.sup.3 of 60% sulphuric acid are heated at 85.degree. C. for 8
hours. The mixture is hydrolysed with 100 cm.sup.3 of water and the pH is
brought to 8-9 by addition of sodium hydrogen carbonate. A brown
precipitate is filtered off and dissolved in 300 cm.sup.3 of
dichloromethane. The organic phase is washed with 200 cm.sup.3 of water
and dried over magnesium sulphate, and then concentrated to dryness under
reduced pressure (2.7 kPa) at a temperature close to 40.degree. C. 12 g of
a wet brown solid are obtained, which solid is chromatographed on a column
7.7 cm in diameter containing 1.9 kg of silica (0.02-0.045). The elution
is carried out with a dichloromethane/methanol (95/5) mixture, at a
pressure of 150 kPa, collecting 60 cm.sup.3 fractions. The homogeneous
fractions are pooled and concentrated to dryness under reduced pressure
(2.7 kPa) at a temperature close to 40.degree. C. 5.4 g of
2-chloro-8-oxo-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide
are obtained in the form of a white solid melting at 234.degree. C.
A mixture of 3 g of
2-chloro-8-oxo-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide
in 1000 cm.sup.3 of methanol is stirred under argon until complete
dissolution. 10 mg of bromocresol green are added, and 0.946 g of sodium
cyanoborohydride in 10 cm.sup.3 of methanol is added dropwise. When the
reaction mixture becomes blue-green, a saturated solution of hydrochloric
ethanol is added dropwise until the yellow colour disappears. The mixture
is kept stirring at room temperature for 48 hours, and then concentrated
to dryness under reduced pressure (2.7 kPa) at a temperature close to
40.degree. C. The residue is taken up in 150 cm.sup.3 of water and the pH
is brought to 8-9 by addition of sodium hydrogen carbonate. The aqueous
phase is extracted with three times 150 am.sup.3 of dichloromethane. The
organic phases are dried over is magnesium sulphate and concentrated to
dryness under reduced pressure (2.7 kPa) at a temperature close to
40.degree. C. 2.5 g of a white solid are obtained, which solid is
recrystallized from 55 cm.sup.3 of acetonitrile. 1.99 g of
(R,S)-2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-car
boxamide are obtained in the form of a white powder melting at 201.degree.
C.
The enantiomers of
(R,S)-2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-car
boxamide can be separated in the following manner:
2 g of
(R,S)-2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-car
boxamide are separated by high-performance liquid chromatography on a
CHIRALPAK AD stationary chiral phase (4.6.times.250 mm). The mobile phase
is a 50/50 mixture of heptane and ethanol, the flow rate is 1 ml/min.
1.164 g of the dextrorotatory enantiomer [.alpha.].sub.D.sup.20
=+14.8.+-.0.6 (c=0.5; dimethylformamide) and 1.053 g of the laevorotatory
enantiomer [.alpha.].sub.D.sup.20 =-15.8.+-.0.6 (c=0.5; dimethylformamide)
are obtained.
3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile is prepared as
described in European Patent Application EP 124 384.
EXAMPLE 8
A suspension of 1.36 g of
(R,S)-2-chloro-8-hydroxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-car
boxamide and 0.975 g of p-toluenesulphonic acid monohydrate in 160 cm.sup.3
of toluene is heated at the reflux temperature of toluene for 16 hours.
The reaction mixture is concentrated to dryness under reduced pressure (2.7
kPa) at a temperature close to 55.degree. C. 0.9 g of a yellow solid is
obtained which is recrystallized from 10 cm.sup.3 of isopropanol. 0.469 g
of 2-chloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide is obtained
in the form of a yellow solid melting at 195.degree. C.
EXAMPLE 9
A mixture of 20 g of
3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 56.8 g of
N-chlorosuccinimide in 1600 cm.sup.3 of acetonitrile is heated at the
reflux temperature of acetonitrile for 3 hours. 150 cm.sup.3 of
hydrochloric acid (1 N) and 150 cm.sup.3 of water are added to the
reaction mixture. The reaction mixture is concentrated to dryness under
reduced pressure (2.7 kPa) at a temperature close to 55.degree. C. The
residue obtained is taken up in 200 cm.sup.3 of water, and the pH is
brought to 8-9 by addition of sodium hydrogen carbonate as a powder. After
filtration, 29.23 g of a light brown solid are obtained, which solid is
chromatographed on a column 10 cm in diameter containing 2000 g of silica
(0.02-0.045). The elution is carried out with dichloromethane, collecting
70 cm.sup.3 fractions. The homogeneous fractions are pooled and
concentrated to dryness under reduced pressure (2.7 kPa) at a temperature
close to 40.degree. C. 20.75 g of
2,7,7-trichloro-8-oxo-3-pyridin-3-yl-5,6,7-trihydroindolizine-1-carbonitri
le are thus obtained in the form of a powder melting at 228.degree. C.
6.48 g of palladium on carbon (10%) in suspension in ethanol are added to a
mixture of 20.75 g of
2,7,7-trichloro-8-oxo-3-pyridin-3-yl-5,6,7-trihydroindolizine-1-carbonitri
le, 2000 cm.sup.3 of ethanol, 600 cm.sup.3 of acetic acid and 5.2 cm.sup.3
of hydrochloric acid (12 N). A stream of hydrogen is passed through for 3
hours. The reaction mixture is filtered on Celite and then washed with
twice 100 cm.sup.3 of ethanol. The filtrate is concentrated to dryness
under reduced pressure (2.7 kPa) at a temperature close to 60.degree. C.
The orange-coloured solid obtained is taken up in 200 cm.sup.3 of water,
and the pH is brought to 8-9 by addition of sodium hydrogen carbonate, and
then filtered and washed with twice 20 cm.sup.3 of water. 0.5 g of
2-chloro-3-pyridin-3-yl-5,6,7-trihydro-8-oxoindolizine-1-carbonitrile is
thus obtained in the form of a yellow solid melting at a temperature
greater than 260.degree. C.
A mixture of 2.717 g of
2-chloro-3-pyridin-3-yl-5,6,7-trihydro-8-oxoindolizine-1-carbonitrile, 1
cm.sup.3 of hydrochloric methanol (3.8 N), and 5.5 cm.sup.3 of trimethyl
orthoformate in 200 cm.sup.3 of methanol is heated at the reflux
temperature of methanol for 12 hours. The reaction mixture is concentrated
to dryness under reduced pressure (2.7 kPa) at a temperature close to
40.degree. C. The beige solid obtained is taken up in 50 cm.sup.3 of water
and the pH is brought to 8-9 by addition of sodium hydrogen carbonate.
After filtration, 2.6 g of a beige powder are obtained, which powder is
chromatographed on a column 4 cm in diameter containing 35 g of silica
(0.02-0.045). The elution is carried out with dichloromethane and then
with a dichloromethane/ethyl acetate (80/20) mixture, collecting 50
cm.sup.3 fractions. The homogeneous fractions are pooled and concentrated
to dryness under reduced pressure (2.7 kPa) at a temperature close to
40.degree. C. 1.7 g of
2-chloro-8-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile are
thus obtained in the form of a white powder melting at 229.degree. C.
0.12 g of palladium on carbon (10%) is added to a mixture of 0.55 g of
2-chloro-8-methoxy-3-pyridin-3-yl-5,6-dihydroindolizine-1-carbonitrile in
5 cm.sup.3 of methanol. A stream of hydrogen is passed through for 14
hours. The reaction mixture is filtered on Celite and then washed with
twice 40 cm.sup.3 of methanol. The filtrate is concentrated to dryness
under reduced pressure (2.7 kPa) at a temperature close to 50.degree. C.
0.49 g of a beige semicrystallized product is obtained, which product is
chromatographed on a column 2 cm in diameter containing 150 g of silica
(0.02-0.045). The elution is carried out with a dichloromethane/methanol
(95/5) mixture, collecting 15 cm.sup.3 fractions. The homogeneous
fractions are pooled and concentrated to dryness under reduced pressure
(2.7 kPa) at a temperature close to 40.degree. C. 0.12 g of
2-chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitr
ile is thus obtained in the form of a yellow oil.
Rf=0.49 dichloromethane/methanol (95/5).
A mixture of 0.23 g of
2-chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitr
ile and 0.16 g of potassium hydroxide in 15 cm.sup.3 of tert-butanol is
heated at the reflux temperature of tert-butanol for 12 hours. The
reaction mixture is concentrated to dryness under reduced pressure (2.7
kPa) at a temperature close to 50.degree. C. The oil obtained is taken up
in 7 cm.sup.3 of water and extracted with four times 30 cm.sup.3 of
dichloromethane. The organic phases are dried over magnesium sulphate and
then concentrated to dryness under reduced pressure (2.7 kPa) at a
temperature close to 40.degree. C. 0.125 g of a vitreous residue is
obtained which is chromatographed on a column 2 cm in diameter containing
100 g of silica (0.02-0.045). The elution is carried out with a
dichloromethane/methanol (95/5) mixture, collecting 40 cm.sup.3 fractions.
The homogeneous fractions are pooled and concentrated to dryness under
reduced pressure (2.7 kPa) at a temperature close to 40.degree. C. 0.09 g
of a semisolid is obtained which is recrystallized from 1.1 cm.sup.3 of
acetonitrile. 0.0277 g of
2-chloro-8-methoxy-3-pyridin-3-yl-5,6,7,8-tetrahydro-indolizine-1-carboxam
ide is thus obtained in the form of a white powder melting at 166.degree.
C.
3-Pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile is described in
Patent EP 124 384.
EXAMPLE 10
8-Oxo-2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile
is prepared as described in Example 3.
A mixture containing 2 g of
8-oxo-2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile
and 4.81 cm.sup.3 of benzylamine is heated at a temperature of 150.degree.
C. for 20 minutes. The mixture is then hydrolysed with 50 cm.sup.3 of
water and extracted with three times 50 cm.sup.3 of dichloromethane. The
organic phases are washed with twice 50 cm.sup.3 of water and then dried
over magnesium sulphate and then filtered and concentrated to dryness
under reduced pressure (2.7 kPa) at a temperature close to 40.degree. C.
5.17 g of a brown oil are obtained, which oil is chromatographed on a
column 4.2 cm in diameter containing 430 g of silica (0.02-0.045). The
elution is carried out with dichloromethane/methanol (95/5), collecting 30
cm.sup.3 fractions. The homogeneous fractions are pooled and concentrated
to dryness under reduced pressure (2.7 kPa) at a temperature close to
40.degree. C. 1.14 g of
8-amino-2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitril
e are obtained in the form of a yellow oil.
Rf=0.51 dichloromethane/methanol (95/5).
1.56 cm.sup.3 of triethylamine and 0.625 g of chloroacetyl chloride are
added to a mixture containing 1 g of
8-amino-2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitril
e in 50 cm.sup.3 of dichloromethane. The reaction mixture is kept stirring
at room temperature for 24 hours and is then washed with three times 100
cm.sup.3 of water. The organic phase is dried over magnesium sulphate and
then filtered and concentrated to dryness under reduced pressure (2.7 kPa)
at a temperature close to 40.degree. C. 0.92 g of a black residue is
obtained which is chromatographed on a column 2.5 cm in diameter
containing 150 g of silica (0.02-0.045). The elution is carried out with a
dichloromethane/methanol (95/5) mixture, collecting 10 cm.sup.3 fractions.
The homogeneous fractions are pooled and concentrated to dryness under
reduced pressure (2.7 kPa) at a temperature close to 40.degree. C. 0.78 g
of a brown solid is obtained which is then recrystallized with 35 cm.sup.3
of acetonitrile. 0.385 g of
2-chioro-N-(2-chloro-1-cyano-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizin-8-
yl)acetamide is thus obtained in the form of a pale yellow powder melting
at 238.degree. C.
The present invention also relates to the pharmaceutical compositions for
the treatment and/or prophylaxis of conditions in which one or more
viruses of the herpes family are involved and/or in which the cytokines,
including TNF.sub..alpha., are involved, containing a pyrrole derivative
of general formula (I) or a pyrrole derivative of structure (I'),
optionally in the form of is a salt, in the pure state or in the form of a
combination with one or more compatible and pharmaceutically acceptable
diluents or adjuvants.
The pharmaceutical compositions according to the invention are capable of
slowing the progression to the disease or of reducing its severity in the
infected subjects.
They are capable of preventing or slowing, in immunosuppressed subjects,
the progression of subjects infected with a virus of the herpes family to
a worsened state of the disease.
The pharmaceutical compositions according to the invention are also capable
of inhibiting the replication of retroviruses and therefore of slowing the
progression to the disease and of reducing its severity in the infected
subjects. In particular, in the case of HIV infections, by inhibiting the
replication of this virus, they are capable of slowing the progression to
AIDS or of reducing its severity in the infected subjects. The
pharmaceutical compositions according to the invention can be used for
preventive or curative purposes. "Preventive" is understood to mean the
preventing of progression in subjects exhibiting immunodeficiency and/or
infected with retroviruses.
Of course, in the case of treatment in immunosuppressed individuals, the
constitution of these compositions will be adapted to the specific case of
the digestive tract of these subjects.
The compositions can be used by the oral, parenteral, topical or rectal
route.
Sterile compositions for parenteral administration may be preferably
solutions which are aqueous or nonaqueous, suspensions or emulsions. As
solvent or vehicle, there may be used water, propylene glycol,
polyethylene glycol, vegetable oils, in particular olive oil, injectable
organic esters, for example ethyl oleate or other suitable organic
solvents. These compositions may also contain adjuvants, in particular
wetting, isotonizing, emulsifying, dispersing and stabilizing agents.
Sterilization can be achieved in several ways, for example by aseptisizing
filtration, by incorporating sterilizing agents into the composition, by
irradiation or by heating. They can also be prepared in the form of solid
sterile compositions which can be dissolved at the time of use in a
sterile injectable medium.
As solid compositions for oral administration, there may be used tablets,
pills, powders or granules. In these compositions, the active product
according to the invention (optionally combined with another
pharmaceutically compatible product) is mixed with one or more inert
diluents or adjuvants, such as sucrose, lactose or starch. These
compositions may also comprise substances other than diluents, for example
a lubricant such as magnesium stearate.
As liquid compositions for oral administration, there may be used emulsions
which are pharmaceutically acceptable, solutions, suspensions, syrups,
elixirs containing inert diluents such as water or paraffin oil. These
compositions may also comprise substances other than the diluents, for
example wetting, sweetening or flavouring products.
The compositions for topical administration may be for example creams,
ointments or lotions.
The compositions for rectal administration are suppositories or rectal
capsules, which contain, in addition to the active ingredient, excipients
such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
In general, the doctor will determine the dosage judged most appropriate
according to the age, weight and factors specific to the product and to
the subject to be treated. Generally, in adults, the doses are between 25
and 2000 mg per day.
It has, furthermore, been shown that the pyrrole derivatives of general
formula (I) and the pyrrole derivatives of structure (I') act in synergy
when they are combined with other antiviral agents active on viruses of
the herpes family or when they are combined with other antiretrovirus
agents. The present invention also relates to the combinations consisting
of a pyrrole derivative of general formula (I) or of a pyrrole derivative
of structure (I'), and of an active ingredient known for its activity on
viruses of the herpes family or else known for its anti-retrovirus
activity, optionally in the presence of pharmaceutically acceptable
excipients.
The agents known for their activity on viruses of the herpes family which
may be combined are chosen from agents which are compatible and chemically
inert towards the pyrrole derivative according to the invention. In a
non-limiting manner, these agents are chosen, for example, from cidofovir,
ganciclovir, foscarnet, GS930 and 1263W94 and the like.
The antiretrovirus agents which can be combined are chosen from agents
which are compatible and chemically inert towards the derivatives
according to the invention. Without implying any limitation, these agents
are chosen from inhibitors of reverse transcriptase [zidovudine (AZT),
didanosine (DDI), dideoxycytidine (DDC), lamivudine (3TC), TIBO,
neviparine, PMEA and the like], among the protease inhibitors [for example
saquinovir, ABT-538, MK-639 and the like], or from tat and rev protein
inhibitors.
The pharmaceutical compositions comprising such combinations are also
within the scope of the present invention.
The following example given with no limitation being implied illustrates a
composition according to the invention.
EXAMPLE
(R,S)-2-chloro-8-hydroxy-3-(pyridin- 25 mg
3-yl)-5,6,7,8-tetrahydroindolizine-
1-carboxamide
Magnesium stearate: 1% 2 mg
ACDISOL: 1% 2 mg
Colloidal silica: 0.5% 1 mg
Lactose 170 mg
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